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      Altered Ca 2+ Homeostasis in Human Uremic Skeletal Muscle: Possible Involvement of cADPR in Elevation of Intracellular Resting [Ca 2+]


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          Background: Patients with chronic renal failure may develop muscle weakness and fatigability due to disorders of skeletal muscle function, collectively known as the uremic myopathy. Cyclic adenosine diphosphate-ribose (cADPR), an endogenous metabolite of β-NAD<sup>+</sup>, activates Ca<sup>2+</sup> release from intracellular stores in vertebrate and invertebrate cells. The current study investigated the possible role of cADPR in uremic myopathy. Methods: We have examined the effect of cADPR on myoplasmic resting Ca<sup>2+</sup> concentration ([Ca<sup>2+</sup>]<sub>i</sub>) in skeletal muscle obtained from control subjects and uremic patients (UP). [Ca<sup>2+</sup>]<sub>i</sub> was measuredusing double-barreled Ca<sup>2+</sup>-selective microelectrodes in muscle fibers, prior to and after microinjections of cADPR. Results: Resting [Ca<sup>2+</sup>]<sub>i</sub> was elevated in UP fibers compared with fibers obtained from control subjects. Removal of extracellular Ca<sup>2+</sup>, or incubation of cells with nifedipine, did not modify [Ca<sup>2+</sup>]<sub>i</sub> in UP or control fibers. Microinjection of cADPR produced an elevation of [Ca<sup>2+</sup>]<sub>i</sub> in both groups of cells. This elevation was not mediated by Ca<sup>2+</sup> influx, or inhibited by heparin or ryanodine. [cADPR]<sub>i</sub> was determined to be higher in muscle fibers from UP compared to those from the control subjects. Incubation of cells with 8-bromo-cADPR, a cADPR antagonist, partially reduced [Ca<sup>2+</sup>]<sub>i </sub>in UP muscle fibers and blocked the cADPR-elicited elevation in [Ca<sup>2+</sup>]<sub>i</sub> in both groups of muscle cells. Conclusion: Skeletal muscles of the UP exhibit chronic elevation of [Ca<sup>2+</sup>]<sub>i</sub> that can be partially reduced by application of 8-bromo-cADPR. cADPR was able to mobilize Ca<sup>2+</sup> from intracellular stores, by a mechanism that is independent of ryanodine or inositol trisphosphate receptors. It can be postulated that an alteration in the cADPR-signaling pathway may exist in skeletal muscle of the patients suffering from uremic myopathy.

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          Most cited references21

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          Ca(2+)-induced Ca2+ release in sea urchin egg homogenates: modulation by cyclic ADP-ribose.

          Calcium-induced calcium release (CICR) may function widely in calcium-mediated cell signaling, but has been most thoroughly characterized in muscle cells. In a homogenate of sea urchin eggs, which display transients in the intracellular free calcium concentration ([Ca2+]i) during fertilization and anaphase, addition of Ca2+ triggered CICR. Ca2+ release was also induced by the CICR modulators ryanodine and caffeine. Responses to both Ca2+ and CICR modulators (but not Ca2+ release mediated by inositol 1,4,5-trisphosphate) were inhibited by procaine and ruthenium red, inhibitors of CICR. Intact eggs also displayed transients of [Ca2+]i when microinjected with ryanodine. Cyclic ADP-ribose, a metabolite with potent Ca(2+)-releasing properties, appears to act by way of the CICR mechanism and may thus be an endogenous modulator of CICR. A CICR mechanism is present in these nonmuscle cells as is assumed in various models of intracellular Ca2+ wave propagation.
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            Dantrolene inhibition of sarcoplasmic reticulum Ca2+ release by direct and specific action at skeletal muscle ryanodine receptors.

            The skeletal muscle relaxant dantrolene inhibits the release of Ca2+ from the sarcoplasmic reticulum during excitation-contraction coupling and suppresses the uncontrolled Ca2+ release that underlies the skeletal muscle pharmacogenetic disorder malignant hyperthermia; however, the molecular mechanism by which dantrolene selectively affects skeletal muscle Ca2+ regulation remains to be defined. Here we provide evidence of a high-affinity, monophasic inhibition by dantrolene of ryanodine receptor Ca2+ channel function in isolated sarcoplasmic reticulum vesicles prepared from malignant hyperthermia-susceptible and normal pig skeletal muscle. In media simulating resting myoplasm, dantrolene increased the half-time for 45Ca2+ release from both malignant hyperthermia and normal vesicles approximately 3.5-fold and inhibited sarcoplasmic reticulum vesicle [3H]ryanodine binding (Ki approximately 150 nM for both malignant hyperthermia and normal). Inhibition of vesicle [3H]ryanodine binding by dantrolene was associated with a decrease in the extent of activation by both calmodulin and Ca2+. Dantrolene also inhibited [3H]ryanodine binding to purified skeletal muscle ryanodine receptor protein reconstituted into liposomes. In contrast, cardiac sarcoplasmic reticulum vesicle 45Ca2+ release and [3H]ryanodine binding were unaffected by dantrolene. Together, these results demonstrate selective effects of dantrolene on skeletal muscle ryanodine receptors that are consistent with the actions of dantrolene in vivo and suggest a mechanism of action in which dantrolene may act directly at the skeletal muscle ryanodine receptor complex to limit its activation by calmodulin and Ca2+. The potential implications of these results for understanding how dantrolene and malignant hyperthermia mutations may affect the voltage-dependent activation of Ca2+ release in intact skeletal muscle are discussed.
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              Synthesis and degradation of cyclic ADP-ribose by NAD glycohydrolases.

              Cyclic adenosine diphosphoribose (cADPR), a recently discovered metabolite of nicotinamide adenine dinucleotide (NAD), is a potent calcium-releasing agent postulated to be a new second messenger. An enzyme that catalyzes the synthesis of cADPR from NAD and the hydrolysis of cADPR to ADP-ribose (ADPR) was purified to homogeneity from canine spleen microsomes. The net conversion of NAD to ADPR categorizes this enzyme as an NAD glycohydrolase. NAD glycohydrolases are ubiquitous membrane-bound enzymes that have been known for many years but whose function has not been identified. The results presented here suggest that these enzymes may function in the regulation of calcium homeostasis by the ability to synthesize and degrade cADPR.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                August 2005
                27 June 2005
                : 100
                : 4
                : p51-p60
                aCentro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas, Venezuela; bDepartment of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Mass., USA, and cDepartamento de Medicina Interna, Centro Médico Militar Paramacay, Valencia/Carabobo, Venezuela
                85444 Nephron Physiol 2005;100:p51–p60
                © 2005 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                : 21 October 2004
                : 15 February 2005
                Page count
                Figures: 7, References: 45, Pages: 1
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/85444
                Self URI (text/html): https://www.karger.com/Article/FullText/85444
                Self URI (journal page): https://www.karger.com/SubjectArea/Nephrology
                Original Paper

                Cardiovascular Medicine,Nephrology
                Skeletal muscle,Heparin,Uremia,Uremic patients,Ryanodine,Cyclic adenosine diphosphate-ribose,Calcium homeostasis,8-Bromo-cADPR


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